Tyrosinemia type 1 belongs to a group of rare, inherited metabolic disorders caused by impaired breakdown of the amino acid, tyrosine. Tyrosine is one of the 20 amino acids found in all proteins. When the body has used all the tyrosine it needs, primarily for protein production, the excess is normally broken down. This process occurs in several stages. In tyrosinemia type 1 this metabolic process is defective so that toxic products accumulate, thereby causing liver and kidney damage.

There are several different types of tyrosinemia. Tyrosinemia type 1 is both the most prevalent and most severe form, and this is the one described here. Tyrosinemia type 1 has historically been divided into two forms, acute and chronic. The disorder was first described in 1956 by Margaret D. Baber. In 1965, Swedish physician Rolf Zetterström and associates published the first detailed description of the disorder and its variants, and in 1977 Bengt Lindblad and his team described the defective enzyme underlying the condition.

In Sweden, the estimated incidence of tyrosinemia in newborns is approximately one per 100,000. The global variation is wide and the number may be lower in some countries. The condition is considerably more prevalent in one region of Canada than in other parts of the world. In Sweden, approximately one infant per year is diagnosed with tyrosinemia type 1 and, unlike some other countries, the chronic form is more common than the acute.

Tyrosinemia type 1 is caused by mutations in the FAH gene, which governs the production of the enzyme fumarylacetoacetase (FAH). FAH is located on the long arm of chromosome 15 (15q25.1). Fumarylacetoacetase has an important role in breaking down the amino acid tyrosine. Currently (2013) about 40 FAH mutations are known. There is no clear association between the mutation (genotype) the individual has and the severity of the disease (phenotype).

When FAH does not function normally, there is an accumulation of several metabolic products from the breakdown of tyrosine. One such product is fumarylacetoacetate (FAA). FAA is extremely toxic and damages many different functions in the cells where it accumulates, particularly in the liver and kidneys.

FAA is also converted into succinylacetone, which inhibits another enzyme. This enzyme deficiency causes the same symptoms as acute intermittent porphyria, including abdominal pains, high blood pressure and neurological symptoms. Separate information on acute intermittent porphyria is available in the rare disease database of the Swedish National Board of Health and Welfare.

The inheritance pattern of tyrosinemia type 1 is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Infants who are discovered to have the condition during the neonatal screening programme for metabolic disorders (PKU test in Sweden) and receive the correct treatment, develop few or none of the symptoms which are described here.

Children with tyrosinemia type 1 who do not receive treatment may present with a number of different symptoms. These include failure to thrive, fever, vomiting, diarrhoea, enlarged liver or liver failure, excessive abdominal fluids (ascites), jaundice, impaired kidney function, rickets, and liver tumours.

Without treatment, children with the acute form of tyrosinemia type 1 become ill during the first few months of life. Symptoms include failure to gain weight, fever, diarrhoea, bloody stools and vomiting. The liver is enlarged and the child may develop jaundice. There may also be an increased tendency to bleed, and to frequent nose bleeds. Other symptoms include an enlarged spleen, and swollen abdomen and legs. Seriously ill children may have a particular smell, reminiscent of cabbage. Without treatment the condition quickly becomes life-threatening owing to liver failure and coagulation deficiencies.

In the untreated chronic form, symptoms appear gradually and are less severe. Some children develop symptoms around the age of one, while in others the condition may not appear until school age. The abdomen becomes distended owing to liver and spleen enlargement, and rickets causes bone abnormalities. The primary cause of rickets is impaired renal function, of a type that resembles a kidney defect called Fanconi syndrome. Impaired liver function with ensuing complications is common. If untreated, the chronic form of the disease often results in malignant liver tumours which cause premature death.

An accumulation of succinylacetone can sometimes give rise to the same symptoms as in acute intermittent porphyria, a disorder caused by impaired production of the red blood pigment heme. In such cases children experience abdominal pain, polyneuropathy (a disease causing peripheral nerve damage), high blood pressure and sometimes paralysis of the respiratory musculature. This can cause severe respiratory failure which requires a mechanical ventilator. High blood concentrations of tyrosine may also cloud the corneas, causing impaired vision. The disease is also associated with a thickening of the cardiac muscle, which can be detected by ultrasonography.

As modern treatment results in improved general health and life expectancy, it has been discovered that children with the condition may go on to develop neuropsychiatric symptoms.

Since November 2010 a test for tyrosinemia type 1 has been included in the Swedish general neonatal screening programme for inherited metabolic disorders (known as PKU screening). For this reason it has become increasingly rare in Sweden for children with the condition to be discovered only after they develop symptoms. A diagnosis is confirmed through a urine test to establish the presence of organic acids (particularly succinylacetone), through blood tests for concentrations of amino acids and alpha-fetoprotein, and signs of liver and kidney damage.

As the disease can cause a wide variation in symptoms within the same family, healthy siblings who have not previously been screened should be tested, bearing in mind the risk of liver tumours.

It is possible to make a diagnosis based on DNA testing. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known. In most cases the mutation can be identified and this should be done well in advance of a pregnancy. In prenatal diagnosis, levels of succinylacetone in the amniotic fluid and the FAH enzyme in amniotic fluid cells can also be measured.

Tyrosinemia type 1 can be treated with a specific medication called nitisinone, a special diet including protein replacements, and liver transplantation. Nitisinone blocks the breaking down of tyrosine in the second stage of the process. This means that the toxins which develop later in the process cannot accumulate. At the same time, tyrosine levels in the blood rise, which needs to be regulated by dietary treatment.

A child with tyrosinemia type 1 should be treated at a medical centre specializing in inherited metabolic diseases, where specialist physicians and dieticians collaborate with geneticists, chemists, psychologists and counsellors, and where there is regular contact with ongoing research and development into the disease. The centre should be responsible for making a treatment and follow-up plan, which is followed and continuously updated. The disease is so rare that it has not been possible to assess the treatment programme scientifically. For this reason, existing descriptions are based on clinical experience of children with the acute form of the disease.

Regular monitoring can be carried out, at least partly, in the area where the child lives. The number of visits is adjusted to take account of age and symptoms. Planned, regular follow-ups should take place in centres for metabolic diseases where doctors and dieticians can evaluate results, provide new information on diet and treatment and, in collaboration with the person with the disease and his/her relatives, plan future treatment.

In the past, a special diet and liver transplantation were the only treatments for tyrosinemia. Dietary treatment could often normalize liver and kidney function but in the longer term it could not prevent premature death. The discovery of the cause of the clinical symptoms and the beneficial effects of nitisinone has created a revolution in treatment. Modern medication prevents an accumulation of the toxic products.

Nitisinone treatment was introduced in the early 1990s. Since then, survival rates have improved dramatically. Of those children who developed symptoms before the age of two months and received only dietary treatment, approximately 30 per cent survived for a further two years. However, of the children treated with nitisinone in the first month of life, none developed liver disease during a follow-up period of at least five years. Children who develop acute symptoms before the treatment starts improve rapidly after receiving nitisinone, and no new complications develop when treatment is continued. If treatment is interrupted the child becomes ill again and risks serious injury. There is a certain risk of liver tumours if treatment is not started during the first weeks of life.

Dietary restrictions remain an important part of treatment. For this reason it is important that the family has early contact with a dietician with knowledge of the disease. Food energy content should be monitored and the intake of the amino acids phenylalanine and tyrosine should be strictly regulated. The diet should be adjusted to individual needs and the protein content must remain high enough for the child to grow normally. Protein substitutes specially designed for children and adults with tyrosinemia type 1 are available. With the help of blood tests it is possible to monitor the intake of phenylalanine and tyrosine, so that the levels are neither too high nor too low. Treatment is lifelong and requires considerable commitment.

If the liver is severely damaged, there is a risk of acute liver failure, which is a life-threatening condition. Should this complication arise, liver transplantation must be considered. A transplant should also be considered in those few cases where nitisone treatment does not have the intended effect. Transplantation results have been good, but this is a risky treatment that requires lifelong immunosuppressant therapy.

Vitamin D supplements may be considered for the treatment of rickets.

More children than previously thought require testing to identify possible neuropsychiatric symptoms, so they receive appropriate educational support if necessary.

Dietary therapy requires commitment, along with precision, patience, and inventiveness, and despite restrictions it is important that children with tyrosinemia find mealtimes pleasurable. The whole family must be aware of the dietary rules, and the food served to the child should, as far as possible, look the same as for other family members. It is a good idea to have contact with other parents in the same situation to exchange hints and advice on how to help children enjoy their meals despite the restrictions. Sometimes this may be achieved by serving foods that have a high fat and sugar content.

As the clinical picture of the disease has changed and become less serious, and life expectancy has improved, it has become possible to observe new, longer-term effects of the disease. The underlying cause of neuropsychiatric symptoms has not yet been described in detail. For example, the clinical significance of low levels of phenylalanine in the blood of people with tyrosinemia type 1 requires study. Also, as yet only a few pregnancies in women with the disease have been studied.

Current knowledge (2014) of the disease gives no indication that modern gene therapy is likely to replace the current combination of nitisinone and dietary therapy in the future.

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This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.